Project Summary The capacity to response to internal and external stressors is critical for cellular survival throughout life and during aging. Despite the presence of protective mechanisms, cellular damage accrues over an organism?s lifetime, including accumulated damage to the proteome. Such deficits to protein homeostasis have a particularly deleterious effect in neurons, where they contribute to the development and progression of age-associated neurodegenerative diseases, such as Alzheimer?s disease. Cell-intrinsic mechanisms for responding to proteotoxicity have been identified; three major stress responses (the cytoplasmic heat shock response, the endoplasmic reticulum unfolded protein response, and the mitochondrial unfolded protein response) act cell autonomously in neurons and other cell types to ameliorate proteotoxic stress. There is also mounting evidence that neuronal health in this context is modulated by communication from non-neuronal tissues; however, very little is known about the relevant underlying mechanisms. The major objective of the proposed work is to characterize the nature of cell non-autonomous regulation of neuronal proteostasis, using C. elegans as a model. First, we will determine how perturbing stress response pathways in non-neuronal tissues affect neuronal proteostasis. Recent work has shown that activation of each of the three proteostatic stress responses in neurons cell non- autonomously protects peripheral tissues from proteotoxicity; we hypothesize that non-autonomous protection might also occur in the reverse direction, i.e. that activation of these stress responses in non-neuronal tissues can promote neuronal proteostasis, which we will test by in Aim 1. Second, we will more broadly explore mechanisms of periphery-to-neuron communication that alter neuronal proteostasis. We will identify genes that function cell non-autonomously to regulate neuronal proteostasis using a tissue-specific knockdown screening approach in Aim 2. Together these aims are likely to yield insight into the mechanisms by which inter-tissue communication influences neuronal health and could lead to the identification of new therapeutic targets for diseases associated with neuronal proteotoxic stress. The sponsor for the proposed work, Dr. Andrew Dillin, is a renowned expert in proteostasis with an excellent training record; his laboratory at UC Berkeley represents an ideal environment for the applicant to develop the research, mentorship, and communication skills necessary to become an independent investigator.